tbuckley/cabot-search huggingface dataset:
Population-based impact of rurality and neighborhood-level socioeconomic disadvantage on pediatric cancer mortality in Washington State.
Authors: Timothy James Daeeun Ohlsen, David R Doody, Arti D Desai, Beth A Mueller, Eric Jessen Chow
Journal: Journal of Clinical Oncology (2022)

6537 Background: Emerging evidence suggests mortality among children with cancer differs based on socioeconomic factors. The effects of residential location in relation to these factors are not well-characterized. We examined associations of rurality and neighborhood-level socioeconomic (SE) disadvantage with mortality in pediatric patients with cancer. Methods: We conducted a retrospective cohort study using Washington State (WA) Cancer Registry data (1992-2013) linked to state birth (1974-2013) and death records (1992-2013) to identify all children born in WA diagnosed with cancer &lt; 20 years. We defined rural residence as patient addresses within 2010 census tract level rural-urban commuting area (RUCA) codes of ≥4.0 at diagnosis. Neighborhood-level socioeconomic disadvantage was determined using 2010 census block-group level Area Deprivation Index (ADI) quintiles normalized to WA. Patient addresses within the highest ADI quintile were categorized as having SE disadvantage. children in four mutually exclusive groups was compared using Kaplan-Meier analysis, pairwise log rank testing, and Cox proportional hazard ratios (HR): non-rural with SE disadvantage, rural without SE disadvantage, rural with SE disadvantage, and non-rural without SE disadvantage (). Models were adjusted for sex, race and ethnicity, age at diagnosis, birth year, and cancer type. Results: We identified 4,417 children for analysis. Median length of follow up among survivors was 5.0 years (inter-quartile range: 1.0-11.5). SE disadvantaged and 13% were rural. Pairwise log rank tests showed mortality differences among children living in rural, SE disadvantaged, or rural and SE disadvantaged neighborhoods when compared with children without either factor (individual p-values all &lt; 0.005); no other differences were noted. Relative to children in non-rural areas without SE disadvantage, the mortality HR for those in non-rural areas with SE disadvantage was 1.68 (95% confidence intervals [CI] 1.37-2.07). The HR for children in rural areas without SE disadvantage was 1.59 (95% CI 1.19-2.12). The HR for children in rural areas with SE disadvantage was 1.56 (95% CI 1.20-2.03). In sub-analyses, associations for rurality and SE disadvantage remained significant for leukemia mortality, but CNS and solid tumor mortality was only associated with SE disadvantage (but not rural) status. Acute lymphoblastic leukemia mortality was associated with rural (but not SE disadvantage) status. Conclusions: Children with cancer living in socioeconomically disadvantaged and/or rural neighborhoods at diagnosis had higher mortality relative to those in non-rural areas with lower neighborhood deprivation. Associations varied by disease type. The individual effects of SE disadvantage and rurality suggest that interventions should be designed to target both factors.
MEDB-68. Analysis of telomeres length and Alternative Lengthening of Telomeres (ALT) in molecular subgroups of infant medulloblastoma
Authors: Francesca Romana Buttarelli, Simone Minasi, Maria Luisa Garrè, Maura Massimino, Veronica Biassoni, Tobias Goschzik, Torsten Pietsch, Felice Giangaspero
Journal: Neuro-Oncology (2022)

Abstract We investigated the association between the molecular profile and telomere length in a infant medulloblastoma (iMB) cohort, retrospectively studied. Activation of telomeres maintenance mechanisms was analyzed to determine whether the senescence escape triggered by telomere-elongation mechanisms could explain the aggressivity of some iMB belonging to the same molecular subgroup. Interestingly, several telomerase- and ALT-targeted therapies have recently been tested on pediatric cancers and might represent a promising strategy for the future treatment of aggressive telomerase- or ALT-positive iMB. We analyzed a cohort of 50 FFPE tissues from young MB patients (age ≤ 3); IHC, FISH, and an Illumina 850K methylation profile were used to identify molecular subgroups. Telomere length was measured using Telo-quantitative FISH, and image analysis was performed using TFL-Telo software. Three distinct telomere intensity categories (low (L), medium (M), and high (H)) were identified by comparing neoplastic- to endothelial-cell signals in each sample. ATRX loss and TERTp mutation/methylation were investigated using IHC and Sanger sequencing/methylation-specific PCR. SHH-MBs accounted for 59% of our cohort, while Group3/4-MBs accounted for 41%; no WNT-MBs were detected. ALT was found to be activated in 10% of iMBs and was not exclusive to any molecular subgroup, implying that it could be a potential mechanism associated with aggressive behaviour in a subset of iMBs. Promising results have been found in the telomere length distribution among the iMB molecular subgroups: SHH iMBs had a higher frequency of High (H) telomeres length (85%) than NON-SHH/NON-WNT iMBs (p=0.046), which were more frequently associated with Medium (M) telomeres length. CONCLUSIONS: ALT activation in infant MBs (10%) could be a novel target for risk-stratification and personalized therapy. It may be useful to examine ALT as a potential predictor of aggressive behaviour and as a promising novel therapeutic approach for a subset of these tumors in the diagnostic workup.
EPEN-11. Phase 0/I Study of GM-CSF and Intrathecal Trastuzumab In Children With Recurrent Posterior Fossa Ependymoma
Authors: Gregory Norris, Melissa Widener, Vladamir Amani, Andrew Donson, Debra Schissel, Courtney Bruno, Ashley Mettetal, Dominique Ramirez, Daniel Gustafson, Todd Hankinson, Michael Handler, Margaret Macy, Nicholas Foreman, Kathleen Dorris
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Posterior fossa ependymoma (PF EPN) is a pediatric central nervous system malignancy that has a poor outcome to standard therapeutic approaches. The majority of PF EPN have been shown to harbor increased HER2 expression, making it a logical therapeutic target. Trastuzumab is a monoclonal antibody that targets HER2, and sargramostim (GM-CSF) stimulates hematopoietic progenitor cell proliferation. The combination of trastuzumab and GM-CSF has been shown to trigger antibody-dependent cell cytotoxicity in-vitro in patient-derived PF EPN cell lines. METHODS: Children aged 1–21 years with relapsed PF EPN, no ventriculoperitoneal shunt, and no CSF obstruction are eligible for the Phase 0/I single-institution clinical trial at Children’s Hospital Colorado. Stratum 1 involves intrathecal (IT) trastuzumab and subcutaneous (subQ) GM-CSF prior to standard-of-care surgical resection. Stratum 2 involves a 3 + 3 phase I design with serial IT trastuzumab doses, each preceded by three days of GM-CSF, to establish the maximum tolerated dose for IT trastuzumab. RESULTS: Trastuzumab was detected in a sufficient number of tumors after presurgical IT delivery in Stratum 1 to open Stratum 2. Seven patients (3 female) have been enrolled in Stratum 2. Median age at enrollment is 8.1 years (range, 3–20 years). CSF pharmacokinetic analysis demonstrate detectable trastuzumab up to 14 days after IT doses. No dose-limiting toxicities or grade 3 or 4 adverse events have occurred. Four patients completed all planned study therapy and remain progression-free post-therapy (median, 23 months, range, 6-42 months). Three patients progressed on therapy (median, 4 cycles). Biologic correlative studies are in process. CONCLUSIONS: IT trastuzumab penetrates PF EPN tumor tissue and demonstrates an excellent safety profile. Stratum 2 remains open to accrual at Dose Level 2. IT trastuzumab+GM-CSF warrants consideration for a multi-institutional Phase II trial.
OTHR-36. Management of Central Diabetes Insipidus (CDI) with Low-Dose Vasopressin Infusion in Patients with Non-Germinomatous Germ Cell Tumors (NGGCT) Requiring Hyperhydration during Chemotherapy
Authors: Caroline Fitzgerald, Kathryn Matson
Journal: Neuro-Oncology (2022)

Abstract Primary intracranial germ cell tumors (GCT) represent 3-5% of central nervous system tumors with non-germinomatous germ cell tumors (NGGCTs) comprising approximately one-third. Located in the pineal and suprasellar regions, the tumors can cause central diabetes insipidus (CDI). Induction chemotherapy for NGGCT includes ifosfamide. Due to the risk of hemorrhagic cystitis associated with ifosfamide, 3000 mL/m2/day of intravenous fluids is administered. Oral desmopressin (DDAVP), the mainstay of treatment for CDI, has a long duration of action, variable intensity and can lead to hyponatremia and water intoxication due to the retention of large quantities of free water. Therefore, DDAVP is held during hyperhydration resulting in significant diuresis leading to patient discomfort and increased risk for wide electrolyte fluctuations. The volume of dextrose-containing IV fluids also places patients at risk for hyperglycemia and other metabolic disturbances. Patients with NGGCTs and CDI at our institution are admitted to the ICU for ifosfamide cycles due to the need for close monitoring and prompt interventions. ICU admission can delay therapy and potentially places patients in a setting where staff are unfamiliar with chemotherapy administration, increasing the risk of safety-related events. From a cost, resource, and patient care perspective, these admissions are suboptimal. This prompted a search for evidence to maintain patients safely out of the ICU. A literature search provided case studies citing the use of low-dose IV vasopressin. In collaboration with our endocrine and pharmacy colleagues we created a protocol to treat patients with CDI receiving chemotherapy with hyperhydration with a low-dose, easily titratable intravenous vasopressin infusion, to keep urine mildly diluted to allow enough diuresis to decrease injury while preventing excessive fluid losses and wide variations in electrolytes.
A novel approach to assessing the effects of smoking on treatment response rate in muscle-invasive bladder cancer.
Authors: Jeromy Gotschall, C. Kendall Major, Linda A. Jacobs, Donna A. Pucci, Abigail Blauch, Steven C. Palmer, Ronac Mamtani
Journal: Journal of Clinical Oncology (2022)

e16554 Background: Cigarette smoking is the strongest modifiable risk factor for bladder cancer and has been implicated in mechanisms of chemotherapy resistance. Prior studies examining tobacco exposure on chemotherapy response were limited by use of retrospective design and self-report assessment of smoking status, potentially under-estimating the association and risking bias towards the null. Cotinine is the central metabolite of nicotine and can be detected in saliva for up to 4 days after tobacco use. In this prospective cohort study, we tested the association between salivary cotinine level and pathologic response to neoadjuvant chemotherapy, assessed post-chemotherapy at the time of cystectomy, among patients with muscle-invasive bladder cancer (MIBC). Methods: Thirty-one patients with MIBC were prospectively recruited and surveyed on their smoking habits. Salivary cotinine was measured during chemotherapy using NicAlert test strips with cotinine concentration &gt; 10ng/mL indicating active smoking (cotinine = 1) and cotinine concentration &lt; 10ng/mL indicating no evidence of active tobacco use (cotinine = 0). Primary outcome was pathologic response at cystectomy, defined as complete response (pT0) or residual disease (pT1-4 or node+). For patients with prior history of tobacco use, the association between pre-chemotherapy cotinine level and post-chemotherapy response at cystectomy was assessed using a chi-squared test and an odds ratio with a 95% confidence interval (CI) using the Baptista-Pike method. Results: Thirty-one patients had cotinine levels measured during chemotherapy and 25 reported prior history of smoking. Of these 25 patients, 17 patients denied active smoking, 2 of whom had cotinine levels = 1 during chemotherapy. Response to chemotherapy by cotinine level among patients with prior history of tobacco use are shown in table 1. One patient declined cystectomy and was excluded from the analysis. The odds ratio of a complete response at cystectomy for patients with cotinine = 0 vs. cotinine = 1 was 3.86 (95% CI: 0.54-22.05) (p = 0.148). The odds ratio of residual disease with cotinine = 0 vs. cotinine = 1 was 0.26 (95% CI: 0.045-1.86) (p = 0.148). Conclusions: Prior smokers with no evidence of active tobacco use during curative chemotherapy were more than three-times as likely to demonstrate a complete response at the time of cystectomy compared to those with evidence of current tobacco use based on salivary cotinine levels. While this study was limited by a small sample size, it highlights a novel approach to tobacco use monitoring and the importance of continued smoking cessation counseling in patients with bladder cancer even after the diagnosis of cancer is made.[Table: see text]
Driver mutations and air pollution in advanced non-small cell lung cancer (NSCLC) at two reference hospitals in Mexico City.
Authors: Eduardo Sanchez, Raul Rogelio Trejo Rosales, Yuly Andrea Remolina Bonilla, Juan José Sánchez Hernández, Amairany Guadalupe Vélez Martínez, Dulce Angelica De Jesus Hernandez, Miriam Najar, Nestor Javier Lizcano Aguilar, Marco Antonio Hernandez Castillo, Andrea Cruz, Santiago Zarroca Palacio
Journal: Journal of Clinical Oncology (2022)

e20545 Background: Currently, precision medicine has allowed the classification of NSCLC according to the profile of driver mutations and the development of highly effective treatments. There is evidence to support the relationship between outdoor air pollution, particularly particulate matter (PM) in outdoor air, with lung cancer incidence and mortality. Smoking is a negative predictor of EGFR mutation, but the effect of air pollution has not been stablished. Methods: We perform a retrospective study in two referral hospitals in Mexico City between 2015 to 2020 to determinate the frequency of key driver mutations in patients with advanced NSCLC and the relation with smoking habit, wood smoke exposure and pollution indexes (PM2.5, PM10, SO2, O3, NO2) according to their place of residence. We used WHO air quality thresholds for air pollutants to classify cases with high or low exposure. Results: A total of 1277 cases were analyzed. The median age at diagnosis was 66 years (range 18-97 years), 53% were females and 49.6% had history of smoking habit. According to histology, 61.6% of cases corresponded to adenocarcinoma, 11.7% were squamous, 1.3% large cell, and 25.4% indeterminate. Wood smoke was assessed in 83.1% of cases and 28.5% had exposure history. Air pollutants were measured in half of cases, high level of exposure for PM2.5, PM10, NO2 and SO2 occurred in 63.2%, 30.8%, 15.6%, 53.4%, respectively. EGFR, ALK and KRAS mutations were evaluated in 85%, 16.7% and 8.6% of patients, respectively. The presence of these mutations was: EGFR 17.1%, ALK 11.1%, and KRAS 16.5%. Patients with EGFR-positive NSCLC were more frequently female (65.1% vs 34.9%, OR 1.8 95%CI 1.4-2.5, p &lt; 0.001) and had no history of tobacco use (35% vs 65%, OR 0.49 95%CI 0.36-0.67, p &lt; 0.001). Wood smoke was not statistically significant. High exposure to PM2.5 was most common in patients with non-mutated EGFR NSCLC (65.3% vs 34.7%, OR 1.7 95%CI 1.2-2.5, p = 0.006). Relationship with other air pollutants were not statistically significant. ALK-positive NSCLC patients tend to be females (68% vs 32%, p = 0.07) and had no history of smoking habit (20.8% vs 79.2% OR 0.28 95%CI 0.1-0.78, p = 0.01). High exposure to SO2 was common (78.6% vs 21.4% p = 0.05). Association in KRAS-positive NSCLS patients were not found. Conclusions: A low rate of key driver mutations assessment was found in this Mexican cohort. Clinical profile of NSCLC EGFR positive is according with previous reports in the literature. Exposure to PM2.5 and SO2 were found associated with EGFR and ALK status in this retrospective study and are hypothesis generating information.
EPEN-18. Oncogenic 3D genome conformations identify novel therapeutic targets in ependymoma
Authors: Konstantin Okonechnikov, Aylin Camgöz, Donglim Esther Park, Owen Chapman, Jens-Martin Hübner, Anne Jenseit, Abhijit Chakraborty, Meghana Pagadala, Rosalind Bump, Sahaana Chandran, Katherina Kraft, Rocio Acuna Hidalgo, Derek Reid, Edwin F Juarez, James T Robinson, Kristian W Pajtler, Till Milde, Nicole Coufal, Michael Levy, Denise Malicki, Shareef Nahas, Matija Snuderl, John Crawford, Robert Wechsler-Reya, Stefan Mundlos, Anthony Schmitt, Hannah Carter, Kulandaimanuvel Antony Michealraj, Sachin A Kumar, Michael D Taylor, Jeremy Rich, Jill Mesirov, Stefan P Pfister, Ferhat Ay, Jesse Dixon, Marcel Kool, Lukas Chavez
Journal: Neuro-Oncology (2022)

Abstract Ependymoma (EPN) is an aggressive pediatric tumor that occurs throughout the central nervous system. The two most aggressive molecular subgroups of EPN are the supratentorial ZFTA-fusion associated group (ST-EPN-ZFTA) and the posterior fossa group A (PF-EPN-A). Although the molecular characteristics underlying the tumorigenesis of these subgroups have been extensively studied, these tumors remain difficult to treat. Hence, innovative therapeutic approaches are urgently needed. Here, we used genome-wide chromosome conformation capture (Hi-C), complemented with CTCF (insulators) and H3K27ac (active enhancers) ChIP-seq, as well as gene expression and whole-genome DNA methylation profiling in primary and relapsed EPN tumors and cell lines, to identify chromosomal rearrangements and regulatory mechanisms underlying aberrant expression of genes that are essential for EPN tumorigenesis. By integrating these heterogenous data types, we have observed the formation of new topologically associated domains (‘neo-TADs’) caused by intra- and inter-chromosomal structural variants in both tumors. In addition, we observed 3D chromatin complexes of regulatory elements, and the replacement of CTCF insulators by DNA hyper-methylation in PF-EPN-A tumors. These tumor-specific 3D genome conformations can be associated with the transcriptional upregulation of nearby genes. Through inhibition experiments we validated that these newly identified genes, including RCOR2, ITGA6, LAMC1, and ARL4C, are highly essential for the survival of patient-derived EPN cell lines in a disease subgroup-specific manner. Thus, our study identifies novel potential therapeutic vulnerabilities in EPN and extends our ability to reveal tumor-dependency genes and pathways by oncogenic 3D genome conformations even in tumors that lack known genetic alterations.
RONC-02. Clinical outcome after craniospinal irradiation with pencil beam scanning proton therapy for children and young adults/adolescents with brain tumors
Authors: Nicolas Bachmann, Miriam Vazquez, Alessandra Bolsi, Suvidya Pachigolla, Claudio De Angelis, Frank Ahlhelm, Antony Lomax, Alessia Pica, Damien Charles Weber
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Craniospinal irradiation (CSI) is an essential treatment component to achieve cure for some brain tumors in children and young adults/adolescents (C-AYAs). Multimodal treatment approaches are however associated with treatment-related late toxicities in these developing patients. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and the brain integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates after CSI for C-AYAs treated with PBSPT. METHODS: We reviewed 71 C-AYAs with a median age of 7.4 years (1.7 – 21.3) who received CSI with PBSPT. Medullobastoma (n=42, 59%) and ependymoma (n=8, 11%) were the most common histologies. Thirty-four (48%) patients presented with metastatic disease at diagnosis. Sixteen (23%) patients were treated for tumor recurrence/progression and 9 (13%) patients underwent re-irradiation. Median prescribed total dose was 54 GyRBE (18 – 60.4) and median craniospinal dose 24 GyRBE (18 – 36.8). Toxicities were recorded according to CTCAE v5.0. RESULTS: With a median follow-up time of 24 months (2 – 195), 12 (17%) patients died due to progressive disease. Eight (11%) patients experienced local failure and 15 (21%) distant failure after PBSPT. Estimated 2-year OS, LC and DC was 86.9%, 86.0% and 80.4%, respectively. Grade 3 acute toxicity (thrombocytopenia, neutropenia, nausea) was observed in 5 (7%) patients. Late grade 3 toxicities (stroke, cataract and CNS necrosis) were observed in 3 (4%) patients, 8, 9 and 16 months after PBSPT, respectively. One (1%) patient developed grade 4 CNS necrosis 8 months after CSI. Late grade ≥3 toxicity free rate was 92.3% at 2 years. No radiation-induced secondary cancer was observed. CONCLUSION: Excellent tumor and brain/spinal distant control and a low late grade ≥3 toxicity rate after CSI were observed in our cohort of C-AYAs treated with PBSPT.
Characterization analysis of gut and bile microbiota for cholangiocarcinomas.
Authors: Wenwen Zhu, Ningning Zhang, Zeyu Wang, Shuwen Zhang, Xiaofen Yue, Linlin Sun, Jiao Sun, Lan Gong, Emad M El-Omar, Wei Lu
Journal: Journal of Clinical Oncology (2022)

e16150 Background: Cholangiocarcinomas (CCAs), which derive from the epithelial cells of the biliary tree, constitute a serious and growing health problem worldwide. Gut and bile microbiota have not been characterized in patients with CCA, and better noninvasive diagnostic approaches for CCA are essential to be established. CA19-9 was the most commonly used tumor marker for CCA; nevertheless, the forecasting performance of CA19-9 remains unsatisfactory. The aim of this study was to investigate the characteristics of gut and bile microbiota combined with CA19-9 in CCA patients. Methods: Fecal samples were collected from 42 CCA patients (16 of the total with Bile samples) and 16 healthy normal controls (HNC). 42 CCA patients were divided into three group according to CA19-9 levels: CCN (CA19-9 negative),CCP (CA19-9 positive: CPL (CA19-9 positive within 10 times) and CPH (CA19-9 positive over 10 times)) groups. DNA was extracted from fecal and bile samples and subjected to 16S rRNA gene analysis. The correlation between gut microbiota and clinical data in CCA group were further analyzed with Spearman rank correlation analysis. Results: Comparing with HNC group, the relative abundance of Firmicutes and Actinobacteriota were significantly decreased, whereas Proteobacteria and Bacteroidota were significantly enriched in CCA group at phylum level (all P &lt; 0.01). Interestingly, Firmicutes/Bacteroidota (F/B) ratio significant decreased in CCA group compared to HNC group(P &lt; 0.05). CA19-9 were inversely correlated with Bifidobacterium, which in turn was associated with Klebsiella in CCA patients. Especially the relative abundance of Klebsiella in CCP group was significantly enriched than CCN group(P &lt; 0.05). Conclusions: Our findings provide evidence supporting Klebsiella may serve as a non-invasive intestinal microbiomarker for CCAs. Combinating with CA19-9, Klebsiella may improve the diagnosis of CCAs as non-invasive approach. Bifidobacterium is likely to be a potential protective factor for anti-tumorgenesis of CCAs.